One third of the U.S. population over the age of 20 (58 million individuals) is obese. The prevalence of obesity in children is approximately 20% and rates of obesity are disproportionately high among Black and Hispanic women. Hypertension, stroke, diabetes and disordered blood lipids have been clearly related to obesity. The widely recognized failure of obesity treatments results not from inability to achieve weight reduction, but from inability to maintain weight loss. We are investigating the metabolic basis for this phenomenon. Recently completed studies have shown that changes in the quantity of stored calories (adipose tissue) above or below that which is "normative" or usual for a given individual, whether lean or obese, are accompanied by changes in energy metabolism in the compartment of non-resting energy expenditure (skeletal muscle). Obese and non-obese individuals have similar responses to experimentially induced changes in caloric storage, "defending" adipose tissue depots of different size by the same metabolic mechanisms. Candidate systems for effecting these changes in energy metabolism include skeletal muscle and the autonomic nervous system. In obese, never-obese, and formerly-obese subjects, measurements will be made of components of (1) Systemic energy metabolism (indirect calorimetry, caloric requirement to maintain body weight, differential excretion of isotopes of heavy water, thermic effect of feeding); (2) Skeletal muscle physiology (oxygen consumption measurements during graded exercise; in vivo metabolic measures of skeletal muscle; muscle biopsies for fiber morphology, capillary density, oxidative and glycolytic enzyme content; (3) Autonomic nervous system activity (heart rate response to serial blockade of cardiac parasympathetic and sympathetic receptors); (4) Body composition (hydrodensitometry, water space by isotope dilution, dual photon beam absorptiometry). (5) Release of candidate signalling proteins from adipose tissue. These measures will be repeated under circumstances of weight stability at weight plateaus equal to, above, and below initial weight. The goal is to identify the cellular and molecular mechanism(s) responsible for the changes in energy metabolism which accompany weight perturbation.